| 31. |
- Krischer, Jeffrey P., et al.
(författare)
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The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:5, s. 980-987
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both. Methods Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4 years of life and then semi-annually thereafter. Results Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5 years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children. Conclusions/interpretation Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.
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| 32. |
- Krischer, Jeffrey P., et al.
(författare)
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The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex, and Family History to the Progression from Multiple Autoantibodies to Type 1 Diabetes:A TEDDY Study Report : A TEDDY Study Report
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:12, s. 3122-3129
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Tidskriftsartikel (refereegranskat)abstract
- This paper seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to T1D risk among autoantibody positive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446_A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium. The risk of progression to T1D was not different among those with or without a family history of T1D (p=0.39) nor HLA-DR-DQ genotypes (p=0.74). Age at developing multiple autoantibodies (HR=0.96 per 1 month increase in age, 95% CI=0.95, 0.97, p<0.001) and the type of first autoantibody (when more than a single autoantibody was the first appearing indication of seroconversion [p=0.006]) were statistically significant. Female sex was also a significant risk factor (p=0.03). Three SNPs were associated with increased diabetes risk (rs10517086_A, [p=0.03], rs1534422_G, [p=0.006], and rs2327832_G in TNFAIP3 [p=0.03]), and one with decreased risk (rs1004446_A in INS, [p=0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied.
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| 33. |
- Köhler, Meike, et al.
(författare)
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Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes : results from the TEDDY study
- 2017
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 1432-5233 .- 0940-5429. ; 54:11, s. 1009-1017
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The onset of clinical type 1 diabetes (T1D) is preceded by the occurrence of disease-specific autoantibodies. The level of autoantibody titers is known to be associated with progression time from the first emergence of autoantibodies to the onset of clinical symptoms, but detailed analyses of this complex relationship are lacking. We aimed to fill this gap by applying advanced statistical models.METHODS: We investigated data of 613 children from the prospective TEDDY study who were persistent positive for IAA, GADA and/or IA2A autoantibodies. We used a novel approach of Bayesian joint modeling of longitudinal and survival data to assess the potentially time- and covariate-dependent association between the longitudinal autoantibody titers and progression time to T1D.RESULTS: For all autoantibodies we observed a positive association between the titers and the T1D progression risk. This association was estimated as time-constant for IA2A, but decreased over time for IAA and GADA. For example the hazard ratio [95% credibility interval] for IAA (per transformed unit) was 3.38 [2.66, 4.38] at 6 months after seroconversion, and 2.02 [1.55, 2.68] at 36 months after seroconversion.CONCLUSIONS: These findings indicate that T1D progression risk stratification based on autoantibody titers should focus on time points early after seroconversion. Joint modeling techniques allow for new insights into these associations.
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| 34. |
- Larsson, Helena, et al.
(författare)
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Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease.
- 2014
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X. ; 15:2, s. 118-126
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Tidskriftsartikel (refereegranskat)abstract
- The Environmental Determinants of Diabetes in the Young (TEDDY) study is designed to identify environmental exposures triggering islet autoimmunity and type 1 diabetes (T1D) in genetically high-risk children. We describe the first 100 participants diagnosed with T1D, hypothesizing that (i) they are diagnosed at an early stage of disease, (ii) a high proportion are diagnosed by an oral glucose tolerance test (OGTT), and (iii) risk for early T1D is related to country, population, human leukocyte antigen (HLA)-genotypes and immunological markers.
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| 35. |
- Larsson, Helena Elding, et al.
(författare)
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Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood : The environmental determinants of diabetes in the young study
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:7, s. 1988-1995
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Tidskriftsartikel (refereegranskat)abstract
- Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. This study explored the relationship between weight or height and development of persistent islet autoimmunity and progression to type 1 diabetes during the first 4 years of life in 7,468 children at genetic risk for type 1 diabetes followed in Finland, Germany, Sweden, and the U.S. Growth data collected every third month were used to estimate individual growth curves by mixed models. Cox proportional hazards models were used to evaluate body size and risk of islet autoimmunity and type 1 diabetes. In the overall cohort, development of islet autoimmunity (n = 575) was related to weight z scores at 12 months (hazard ratio [HR] 1.16 per 1.14 kg in males or per 1.02 kg in females, 95% CI 1.06-1.27, P <0.001, false discovery rate [FDR] = 0.008) but not at 24 or 36 months. A similar relationship was seen between weight z scores and development of multiple islet autoantibodies (1 year: HR 1.21, 95% CI 1.08-1.35, P = 0.001, FDR = 0.008; 2 years: HR 1.18, 95% CI 1.06-1.32, P = 0.004, FDR = 0.02). No association was found between weight or height and type 1 diabetes (n = 169). In conclusion, greater weight in the first years of life was associated with an increased risk of islet autoimmunity.
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| 36. |
- Lee, Hye-Seung, et al.
(författare)
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Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study
- 2014
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Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552. ; 30:5, s. 424-434
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Tidskriftsartikel (refereegranskat)abstract
- Aims The Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. Methods This article describes the details of planning The Environmental Determinants of Diabetes in the Young biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples and reduction of batch effects along with proper sample allocation. Results and conclusion Our design is to reduce potential bias and retain study power while reducing the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples. Copyright (C) 2013 John Wiley & Sons, Ltd.
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| 37. |
- Li, Qian, et al.
(författare)
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Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:3, s. 465-476
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Tidskriftsartikel (refereegranskat)abstract
- Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.
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| 38. |
- Li, Qian, et al.
(författare)
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Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes : the TEDDY Study
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:1, s. 282-292
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Tidskriftsartikel (refereegranskat)abstract
- Children's plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.
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| 39. |
- Lin, Jake, et al.
(författare)
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Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Although the genetic basis and pathogenesis of type 1 diabetes have been studied extensively, how host responses to environmental factors might contribute to autoantibody development remains largely unknown. Here, we use longitudinal blood transcriptome sequencing data to characterize host responses in children within 12 months prior to the appearance of type 1 diabetes-linked islet autoantibodies, as well as matched control children. We report that children who present with insulin-specific autoantibodies first have distinct transcriptional profiles from those who develop GADA autoantibodies first. In particular, gene dosage-driven expression of GSTM1 is associated with GADA autoantibody positivity. Moreover, compared with controls, we observe increased monocyte and decreased B cell proportions 9-12 months prior to autoantibody positivity, especially in children who developed antibodies against insulin first. Lastly, we show that control children present transcriptional signatures consistent with robust immune responses to enterovirus infection, whereas children who later developed islet autoimmunity do not. These findings highlight distinct immune-related transcriptomic differences between case and control children prior to case progression to islet autoimmunity and uncover deficient antiviral response in children who later develop islet autoimmunity.
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| 40. |
- Liu, Xiang, et al.
(författare)
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Distinct growth phases in early life associated with the risk of type 1 diabetes : The teddy study
- 2020
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 43:3, s. 556-562
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7–10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children’s individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D. RESULTS A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only. CONCLUSIONS Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.
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